The intrapleural injection of carrageenan in rats leads to the extravasation of plasma protein with the appearance of a heat-stable (56 C, 30 min.) chemotactic activity; the activity had a molecular weight above 5,000 and was inhibited by monospecific antisera to complement component 5 (anti-C5). Indomethacin treatment (5 mg./kg., i.v.) prior to the carrageenan injection causes approximately the same reduction in the total protein content, immunoreactive material (to anti-C5) and chemotactic activity of the exudate as well as a decline in exudate volume and neutrophil infiltration. Indomethacin did not inhibit neutrophil chemotaxis in vitro in concentrations up to 100 MuM and is unlikely to have a direct action on neutrophils in vivo. The carrageenan-induced inflammatory response of guinea pigs with a genetically total deficiency of complement component 4 appeared to be normal, as determined by the volume, protein content and cell numbers of the inflammatory exudate. The results suggest that the primary action of indomethacin is to suppress extravasation of plasma complement proteins but that it does not inhibit generation of the chemoattractant, a C5a-like material from proteins that do reach the pleural cavity. The chemo-attractant is probably generated through the "alternate pathway" in the complement activation sequence.